Decahydroisoquinoline compounds as excitatory amino acid receptor antagonists

ABSTRACT

This invention provides novel decahydroisoquinoline compounds which are useful as excitatory amino acid receptor antagonists and in the treatment of neurological disorders.

BACKGROUND OF THE INVENTION

The role of excitatory amino acids, such as glutamic acid and asparticacid, as the predominant mediators of excitatory synaptic transmissionin the central nervous system has been well established. Watkins andEvans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges,and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins,Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). Theseamino acids function in synaptic transmission primarily throughexcitatory amino acid receptors. The excitatory amino acids alsoparticipate in a variety of other physiological processes such as motorcontrol, respiration, cardiovascular regulation, sensory perception, andcognition.

Excitatory amino acid receptors are classified into two general types.Receptors that are directly coupled to the opening of cation channels inthe cell membrane of the neurons are termed "ionotropic." This type ofreceptor has been subdivided into at least three subtypes, which aredefined by the depolarizing actions of the selective agonistsN-methyl-D-aspartate (NMDA),α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainicacid (KA). The second general type of receptor is the G-protein orsecond messenger-linked "metabotropic" excitatory amino acid receptor.This second type, when activated by the agonists quisqualate, ibotenate,or trans-1-aminocyclopentane-1,3-dicarboxylic acid, leads to enhancedphosphoinositide hydrolysis in the postsynaptic cell. Both types ofreceptors appear not only to mediate normal synaptic transmission alongexcitatory pathways, but also participate in the modification ofsynaptic connections during development and changes in the efficiency ofsynaptic transmission throughout life. Schoepp, Bockaert, and Sladeczek,Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, BrainResearch Reviews, 15, 41 (1990).

The excessive or inappropriate stimulation of excitatory amino acidreceptors leads to neuronal cell damage or loss by way of a mechanismknown as excitotoxicity. This process has been suggested to mediateneuronal degeneration in a variety of conditions. The medicalconsequences of such neuronal generation makes the abatement of thesedegenerative neurological processes an important therapeutic goal.

Excitatory amino acid excitotoxicity has been implicated in thepathophysiology of a number of neurological disorders. Thisexcitotoxicity has been implicated in the pathophysiology of a cute andchronic neurodegenerative conditions including cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, cerebralischemia, spinal cord trauma, head trauma, Alzheimer's Disease,Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induceddementia, perinatal hypoxia, cardiac arrest, hypoglycemic neuronaldamage, ocular damage and retinopathy, and idiopathic and drug-inducedParkinson's Disease. Other neurological conditions, that are caused byglutamate dysfunction, require neuromodulation. These other neurologicalconditions include muscular spasms, migraine headaches, urinaryincontinence, psychosis, opiate tolerance and withdrawal, anxiety,emesis, brain edema, chronic pain, convulsions, and tardive dyskinesia.The use of a neuroprotective agent, such as an AMPA or NMDA receptorantagonist, is believed to be useful in treating these disorders and/orreducing the amount of neurological damage associated with thesedisorders. The excitatory amino acid antagonists are also useful asanalgesic agents.

Recent studies have shown that AMPA receptor antagonists areneuroprotective in focal and global ischemia models. The competitiveAMPA receptor antagonist NBQX(2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline) has been reportedeffective in preventing global and focal ischemic damage. Sheardown etel., Science, 247, 571 (1900); Buchan et al Neuroreport 2, 473 (1991);LePeillet et al., Brain Research, 571, 115 (1992). The noncompetitiveAMPA receptor antagonist GKYI 52466 has been shown to be an effectiveneuroprotective agent in rat global ischemia models. LaPeillet et al.,Brain Research, 571, 115 (1992).

Recent studies have shown that NMDA receptor antagonists areneuroprotective in animal models of focal cerebral ischemia. Bullock andFujisawa, Journal of Neurotrauma, 9 (supplement 2), S443 (1992); Scattonet al., Cerebrovascular Disease, 1, 121 (1991). These studies have shownthat the competitive NMDA antagonist D-(-)CPP-ene provided protection ina focal cerebral ischemia model in cats, the competitive NMDA antagonistCGS 19755 provided protection in a focal cerebral ischemia model inrats, and the competitive NMDA antagonist LY233053 provided protectionin a CNS ischemia model in rabbits. Bullock et al., Journal of CerebralBlood Flow and Metabolism, 10, 668 (1990); Simon and Shirasho, Annals ofNeurology, 27, 606 (1990); Madden et el., Journal of Neurosurgery, 76,106 (1992). The non-competitive NMDA antagonist dizocilpine providedprotection in models of focal cerebral ischemia in cats and rats. Parket al., Journal of Cerebral Blood Flow and Metabolism, 8, 757 (1988);Park et al., Annals of Neurology, 24, 543 ( 1988). The competitive NMDAantagonist LY274614 is neuroprotective in an animal model ofHuntington's Disease. Schoepp, et al., Journal of Neural Transmission[General Section], 85, 131 (1991).

Several studies have shown that NMDA antagonists are anticonvulsantagents. Meldrum, Epilepsy Research, 12, 189 (1992); Meldrum, Epilepsia,32 (supplement 2), S1 (1991); Chapman and Meldrum, New AntiepilepticDrugs (Epilepsy Research Supplement 3), Elsevier, 39 (1991). Forexample, the competitive NMDA antagonists D-(-)CPP-ene and CGP 37849 areanticonvulsant against sound induced seizures in DBA/2 mice. Chapman,Graham, and Meldrum, European Journal of Pharmacology, 178, 97 (1990).Other studies have shown that NMDA antagonists are analgesics. Forexample, the competitive NMDA antagonist CGS 19755 is analgesic in awarm water tail withdrawal procedure in rhesus monkeys and thecompetitive NMDA antagonist DL-AP5 was analgesic in a mouse formalinmodel. France, Winger, and Woods, Brain Research, 526, 355 (1990);Murray, Cowan, and Larson, Pain, 44, 179 (1991).

These studies strongly suggest that the delayed neuronal degeneration inbrain ischemia involves glutamate excitotoxicity mediated at least inpart by AMPA and/or NMDA receptor activation. Thus, AMPA and NMDAreceptor antagonists may prove useful as neuroprotective agents andimprove the neurological outcome of cerebral ischemia in humans.

SUMMARY OF THE INVENTION

The present invention provides compounds which are antagonists of theexcitatory amino acid receptors. More specifically, the presentinvention relates to compounds that are antagonists of the AMPA and NMDAreceptors. The present invention relates to a compound of the formula##STR1## wherein: R¹ is hydrogen, C₁ -C₁₀ alkyl, arylalkyl,alkoxycarbonyl, aryloxycarbonyl or acyl;

R² is hydrogen, C₁ -C₆ alkyl, substituted alkyl cycloalkyl, orarylalkyl;

R³ is a group of the formula ##STR2## R⁴ is hydrogen, C₁ -C₄ alkyl, CF₃,phenyl, bromo, iodo, or chloro;

or a pharmaceutically acceptable salt thereof.

The invention also provides pharmaceutical formulations comprising acompound of formula I and a pharmaceutically-acceptable carrier,diluent, or excipient.

Further embodiments of the invention include a method of blocking theAMPA or the NMDA excitatory amino acid receptor, as well as methods oftreating a neurological disorder which has been linked to theseexcitatory amino acid receptors, which comprises administering acompound of formula I. Examples of such neurological disorders which aretreated with a formula I compound include cerebral deficits subsequentto cardiac bypass surgery and grafting, stroke, cerebral ischemia,spinal cord trauma, head trauma, Alzheimer's Disease, Huntington'sChorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscularspasms, migraine headaches, urinary incontinence, psychosis,convulsions, perinatal hypoxia, cardiac arrest, hypoglycemic neuronaldamage, opiate tolerance and withdrawal, ocular damage and retinopathy,idiopathic and drug-induced Parkinson's Disease, anxiety, emesis, brainedema, chronic pain, or tardive dyskinesia. The formula I compounds arealso useful as analgesic agents.

DETAILED DESCRIPTION OF THE INVENTION

In the above formula, the term "C₁ -C₁₀ alkyl" represents a straight orbranched alkyl chain having from one to ten carbon atoms. Typical C₁-C₁₀ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl,2-methylpentyl, n-octyl, decyl, and the like. The term "C₁ -C₁₀ alkyl"includes within it the terms "C₁ -C₆ alkyl" and "C₁ -C₄ alkyl". TypicalC₁ -C₆ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, and n-hexyl. TypicalC₁ -C₄ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, and t-butyl.

The term "acyl" represents a hydrogen or C₁ -C₆ alkyl group attached toa carbonyl group. Typical acyl groups include formyl, acetyl, propionyl,butryl, valeryl, and caproyl.

The term "substituted alkyl," as used herein, represents a C₁ -C₆ alkylgroup that is substituted by one or more of the following: hydroxy,fluoro, chloro, bromo, and iodo. Examples of a substituted alkyl groupinclude hydroxymethyl, chloromethyl, bromomethyl iodomethyl,dichloromethyl, dibromomethyl, trichloromethyl, trifluoromethyl,chloroethyl, bromoethyl, perfluoroethyl,2,2,2-trifluoro-1,1-dichloroethyl, 5-hydroxypentyl,2-hydroxy-3,3,3-trifluoropropyl, and the like.

The term "C₁ -C₄ alkoxy" represents groups such as methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, t-butoxy, and like groups. The term"halogen" refers to the fluoro, chloro, bromo, or iodo groups.

The term "substituted phenyl," used herein, represents a phenyl groupsubstituted one or two moieties chosen from the group consisting ofhalogen, hydroxy, cyano, nitro, C₁ -C₆ alkyl, C₁ -C₄ alkoxy,alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl, amino,aminomethyl, trifluoromethyl. Examples of a substituted phenyl groupinclude 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-chlorophenyl,3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl,3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl,4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-nitrophenyl,4-nitrophenyl, 4-cyanophenyl, 4-methylphenyl, 3,4-dimethylphenyl,4-ethylphenyl, 4-methoxyphenyl, 4-carboxyphenyl,4-(hydroxymethyl)phenyl, 4-aminophenyl, 4-(methoxycarbonyl)phenyl,4-(protected carboxy)phenyl, 4-trifluoromethylphenyl, and the like.

The term "aryl" represents groups such as phenyl and substituted phenylas described above. The term "arylalkyl" represents a C₁ -C₄ alkylbearing an aryl group. Representatives of this latter group includebenzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,2-methyl-2-phenylpropyl, (4-chlorophenyl)methyl,(2,6-dichlorophenyl)methyl, (4-hydroxyphenyl)methyl,(2,4-dinitrophenyl)methyl, and the like.

The term "cycloalkyl" represents a C₃ -C₇ cyclic alkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "alkoxycarbonyl" means a carboxyl group having a C₁ -C₆ alkylgroup attached to the carbonyl carbon through an oxygen atom.Representatives of this group include t-butoxycarbonyl andmethoxycarbonyl.

The term "aryloxycarbonyl" represents a carboxyl group bearing an arylgroup attached to the carbonyl carbon through an oxygen atom.Representatives of this group include phenoxycarbonyl,(4-chlorophenoxy)carbonyl, and (3-nitrophenoxy)carbonyl.

While all the formula I compounds of the present invention are believedto be antagonists of the AMPA and the NMDA excitatory amino acidreceptors, certain compounds of the invention are preferred for suchuse. Preferably, R¹ is hydrogen or alkoxycarbonyl; R² is hydrogen or C₁-C₆ alkyl; R³ is a group of the formula, ##STR3## and R⁴ is hydrogen, C₁-C₄ alkyl, CF₃, or phenyl. Representative compounds from this preferredgroup of compounds include: 6-(1(2)H-tetrazole5-yl)decahydroisoquinoline-3-carboxylic acid, ethyl-(1(2)H-tetrazole-5-yl)decahydroisoquinoline-3-carboxylate,2-methoxycarbonyl-6-(1(2)H-tetrazole-5-yl)decahydroisoquinoline-3-carboxylicacid, ethyl2-methoxycarbonyl-6-(1(2)H-tetrazole-5-yl)decahydroisoquinoline-3-carboxylate,6-(3-hydroxyisoxazole-5-yl)decahydroisoquinoline-3-carboxylic acid,ethyl 6-(3-hydroxyisoxazole-5-yl)decahydroisoquinoline-3-carboxylate,2-methoxycarbonyl-6-(3-hydroxyisoxazole-5-yl)decahydroisoquinoline-3-carboxylicacid, ethyl2-methoxycarbonyl-6-(3-hydroxyisoxazole-5-yl)decahydroisoquinoline-3-carboxylate,6-(3-hydroxy-4-methylisoxazole-5-yl)decahydroisoquinoline-3-carboxylicacid,6-(3-hydroxy-4-trifluoromethylisoxazole-5-yl)decahydroisoquinoline-3-carboxylicacid,6-(3-hydroxy-4-phenyl-isoxazole-5-yl)decahydroisoquinoline-3-carboxylicacid, and the like.

Certain compounds of the present invention are more preferred for use asantagonists of the AMPA and the NMDA excitatory amino acid receptors.More preferably, R¹ is hydrogen or alkoxycarbonyl; R² is hydrogen or C₁-C₆ alkyl; and R³ is a group of the formula: ##STR4## Representativecompounds from this preferred group of compounds include:6-(1(2)H-tetrazole-5-yl)decahydroisoquinoline-3-carboxylic acid, ethyl6-(1(2)H-tetrazole-5-yl)decahydroisoquinoline-3-carboxylate,2-methoxycarbonyl-6-(1(2)H-tetrazole-5-yl)decahydroisoquinoline-3-carboxylicacid, ethyl2-methoxycarbonyl-6-(1(2)H-tetrazole-5-yl)decahydroisoquinoline-3-carboxylate,and the like.

Certain compounds of the invention are most preferred for use asantagonists of the AMPA and the NMDA excitatory amino acid receptors.Most preferably, R¹ and R² are hydrogen, and R³ is a group of theformula ##STR5## The compound from this most preferred group is(3S,4aR,6S,8aR)-6-(1(2)H-tetrazole-5-yl)decahydroisoquinoline-3-carboxylicacid.

The formula I compounds of the present invention have the relativestereochemistry shown below: ##STR6## The compounds of the presentinvention possess at least four asymmetric carbon atoms. The asymmetriccenters are the substituted carbon atom adjacent to the ring NR¹ group(3), the carbon atom where R³ is attached to the ring (6), and the twobridgehead carbon atoms (4a and 8a). As such, the compounds can exist asdiastereomers, each of which can exist as the racemic mixture ofenantiomers. The compounds of the present invention include not only theracemates, but also the respective enantiomers. The configuration forthe diastereomer is 3SR,4aRS,6SR,8aRS, and the configuration for theenantiomer is 3S,4aR,6S,8aR. The relative and absolute stereochemistryfor this enantiomer is shown in the following formula. ##STR7##

The compounds of the present may contain a tetrazole ring, which isknown to exist as tautomeric structures. The tetrazole, having thedouble bond on the nitrogen atom at the 1-position and the hydrogen onthe nitrogen atom at the 2-position is as a 2H tetrazole and isrepresented by the following structure. ##STR8## The correspondingtautomeric form wherein the hydrogen is at the nitrogen atom at the1-position and the double bond on the nitrogen atom at the 4-position isnamed as a 1H-tetrazole. The 1H-tetrazole is represented by thefollowing formula. ##STR9## Mixtures of the two tautomers are referredto herein as 1(2)H-tetrazoles. The present invention contemplates bothtautomeric forms as well as the combination of the two tautomers.

The present invention includes the pharmaceutically acceptable salts ofthe compounds defined by formula I. These salts can exist in conjunctionwith the acidic or basic portion of the molecule and can exist as acidaddition, primary secondary, tertiary, or quaternary ammonium, alkalimetal, or alkaline earth metal salts. Generally, the acid addition saltsare prepared by the reaction of an acid with a compound of formula I,wherein R¹ is hydrogen, C₁ -C₁₀ alkyl, or arylalkyl. The alkali metaland alkaline earth metal salts are generally prepared by the reaction ofthe hydroxide form of the desired metal salt with a compound of formulaI, where R² is hydrogen.

Acids commonly employed to form such salts include inorganic acids suchas hydrochloric, hydrobromic, hydriodic, sulfuric, and phosphoric acidas well as organic acids such as para-toluenesulfonic, methanesulfonic,oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic,and acetic acid, and related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate ammonium,monohydrogenphosphate, dihydrogenphosphate, meta-phosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caprate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, hippurate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, α-hydroxybutyrate, glycolate, maleate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,napthalene-2-sulfonate, mandelate, ammonium, magnesium,tetramethylammonium, potassium, trimethylammonium, sodium,methylammonium, calcium, and the like salts.

The formula I compounds of the present invention may be chemicallysynthesized from a common intermediate,6-oxodecahydroisoquinoline-3-carboxylate (VIII). A synthesis of thiscompound was described in U.S. Pat. No. 4,902,695, which is incorporatedherein by reference. An improved synthesis of this intermediate fromd,l-m-tyrosine is shown in Scheme I. ##STR10##

Generally, m-tyrosine (IV) is condensed with formaldehyde to form a6-hydroxy substituted tetrahydroisoquinoline-3-carboxylic acid (V). Thiscompound is esterified at the carboxyl group and blocked on the ringnitrogen with a suitable protecting group to provide a doubly protectedintermediate (VI). This intermediate is reduced to prepare the protected6-hydroxydecahydroisoquinoline-3-carboxylate (VII). The 6-hydroxyl groupis then oxidized to a 6-oxo group to give common intermediate VIII.

More specifically, meta-tyrosine, preferably racemic m-tyrosine, iscondensed with formaldehyde to form the hydroxy substitutedtetrahydroisoquinoline-3-carboxylate (V). This reaction is preferablycarried out in deionized water containing concentrated hydrochloric acidat a temperature of about 55° C. to about 70° C. for about 0.5 to about2 hours. The formula V compound is preferably isolated by cooling thereaction mixture to a temperature of about 3° C. to about 10° C. andremoving the product by filtration.

This compound is preferably protected on both the 3-carboxyl group andthe ring nitrogen. Methods for the protection of amino groups andcarboxyl groups are generally described in McOmie, Protective Groups inOrganic Chemistry, Plenum Press, N.Y., 1973, and Greene and Wutz,Protecting Groups in Organic Synthesis, 2d. ed., John Wiley and Sons,N.Y., 1991. The carboxyl group may be protected as the C₁ -C₆ alkyl,substituted alkyl, or aryl ester. The preferred ester is the C₁ -C₆alkyl ester; the ethyl ester is the most preferred. This ester isprepared by the reaction of intermediate V with a mixture of ethanol andconcentrated sulfuric acid. The reaction is preferably carried out atthe reflux temperature of the solvent for a period of about 16 hours.The ring nitrogen may be protected with an acyl or alkoxycarbonyl group.The preferred protecting groups are t-butoxycarbonyl andmethoxycarbonyl. The most preferred protecting group is methoxycarbonyl.

The 2-methoxycarbonyl protecting group is added using standard syntheticorganic techniques. The ethyl ester of intermediate V is reacted withmethyl chloroformate in the presence of potassium carbonate to formintermediate VI. This reaction is preferably carried out at atemperature of about 0° C. to about 15° C. for a period of about 2hours. Also, the reaction is preferably carried out by the subsequentaddition of potassium carbonate and methyl chloroformate to theesterification reaction mixture. Intermediate VI, wherein R⁵ ismethoxycarbonyl and R⁶ is ethyl, is preferably isolated by extractionand crystallization (ethanol/water).

Intermediate VII is prepared by reduction of intermediate VI. Thepreferred method of reduction is catalytic hydrogenation. Suitablecatalysts include palladium on carbon, platinum on carbon, palladium onalumina, platinum oxide, ruthenium on alumina, rhodium on alumina, orrhodium on carbon. The preferred catalysts are ruthenium on alumina,rhodium on alumina, or rhodium on carbon. The most preferred catalystfor this reduction is rhodium on carbon. Suitable solvents for thereaction include polar organic solvents, such as ethyl acetate,methanol, and ethanol. Ethyl acetate is the preferred solvent for thereaction. The reduction is carried out at a hydrogen pressure of about100 psi to about 1000 psi and at a temperature of about 80° C. to about150° C. When the reaction employs rhodium on alumina, the reaction iscomplete after about 24 hours. The catalyst may be removed by filtrationand the protected 6-hydroxydecahydroisoquinoline-3-carboxylate used inthe next step without isolation.

The 6-hydroxy group of intermediate VII is oxidized to a 6-oxo group inthe preparation of intermediate VIII. This transformation is preferablyaccomplished by the use of a mild oxidizing agent. Suitable mildoxidizing agents include sodium hypochlorite, rutheniumtrichloride/sodium periodate, and ruthenium trichloride/periodic acid.Other oxidizing agents, such as pyridinium chlorochromate (PCC), Jones'reagent, dimethylsulfoxide/N-chlorosuccinimide, tetrapropylammoniumperruthenate (TPAP), pyridine/SO₃, and hypochlorous acid, are alsouseful in effecting this transformation. Preferably, the filtered ethylacetate solution containing intermediate VII is treated with rutheniumtrichloride and water, and the resulting mixture cooled to a temperatureof about -10° C. to about 25° C. The two-phase mixture is next treatedwith periodic acid. After the addition of periodic acid, the reactionmixture is allowed to warm to a temperature of about 20° C. to about 35°C. The desired product, intermediate VIII, is isolated using standardtechniques.

Alternatively, intermediate VI is reduced to prepare intermediate VIII.The preferred method of reduction is catalytic hydrogenation. Thisreaction gives a mixture of 6-hydroxy intermediate VII and 6-ketointermediate VIII. Without further purification, this mixture can beused in a second step to oxidize the 6-hydroxy intermediate VII of themixture to intermediate VIII using the reagents described in theprevious paragraph. Suitable catalysts for the reduction step of thistransformation include palladium on carbon and rhodium on carbon. Thepreferred catalyst is rhodium on carbon. Suitable solvents for thisreaction include polar organic solvents, such as ethyl acetate,methanol, and ethanol. Ethyl acetate is a preferred solvent for thereaction. The reduction is carried out at a hydrogen pressure of about30 psi to about 200 psi and at a temperature of about 70° C. to about90° C. The preferred conditions for this transformation are a hydrogenpressure of about 100 psi and a temperature of about 85° C. When thereaction employs rhodium on carbon, the reaction is complete after about2 hours to about 24 hours. The catalyst may be removed by filtration andthe products used in the next step without further isolation.

The synthetic scheme described in the preceding paragraphs produces amixture of diastereomers, whose relative configurations are illustratedby VIIIa and VIIIb. ##STR11## The predominant diastereomer from thisscheme is intermediate VIIIa. This mixture of diasteromers may beequilibrated to a mixture where VIIIb is the predominant diastereomer bytreatment with a strong base. Suitable strong bases for thisequilibration include metal alkoxides, such as sodium ethoxide andpotassium t-butoxide, and lithium diisopropylamide. The preferred strongbase for the equilibration is sodium ethoxide. When a metal alkoxide isused as a base, the corresponding alcohol may be used as a solvent. Thepreferred solvent for the equilibration is ethanol. When sodium ethoxideand ethanol are used, the equilibration may be carried out at atemperature of about room temperature to about the reflux temperature ofthe solvent. Preferably, the equilibration, when carried out inNaOEt/EtOH, is carried out at about 40° C. This equilibration requiresfrom about one to about six hours. The preferred diastereomer,intermediate VIIIb, is isolated by crystallization from ether (R⁵ ismethoxycarbonyl and R⁶ is ethyl).

The enantiomers of each diastereomer pair of intermediate VIII areresolved using standard resolution techniques. See Jacques, Collet, andWilen, Enantiomers, Racemates, and Resolutions, John Wiley and Sons,N.Y., 1981. The preferred method for resolution of the diastereomers andenantiomers uses chiral amines to form the diastereomeric salts.Suitable chiral amines are described in Jacques et al., Chapter 5, pages253-259. Examples of suitable chiral amines includeR-(+)-α-methylbenzylamine, S-(-)-α-methylbenzylamine,(-)-α-(2-naphthyl)ethylamine, yohimbine, (+)-amphetamine, (-)-ephedrine,strychnine, brucine, quinine, quinidine, cinchonine, cinchonidine, andthe like. The preferred chiral amines are α-methylbenzylamine, brucine,quinine, quinidine, cinchonine, cinchonidine. The more preferred chiralamines are α-methylbenzylamine, brucine, and quinine. The most preferredchiral amine for the resolution of VIIIb is α-methylbenzylamine.

The preferred method of resolving preferred enantiomer is described inthe following. The ethyl ester, intermediate VIIIb where R⁵ ismethoxycarbonyl and R⁶ is ethyl, is hydrolyzed using 5N sodium hydroxideat a temperature of about 25° C. to about 40° C. for a period of about0.5 to about 2 hours. Suitable solvents for this transformation includethe alcohols, such as methanol and ethanol. The free acid may beisolated by extraction with ethyl acetate. The free acid, preferably inethyl acetate solution, is treated with R-(+)-α-methylbenzylamine at atemperature of about 25° C. to about 35° C. for a period of about 15 toabout 60 minutes. Intermediate (-)-VIIIb (R⁶ is hydrogen) precipitatesfrom the reaction solution as the R-(+)-α-methylbenzylamine salt. Thematerial is further purified by reslurrying in warm (45°-50° C.) ethylacetate. In a similar manner, (+)-VIIIb is prepared usingS-(-)-α-methylbenzylamine. The relative and absolute stereochemistry ofthe structures of these intermediates is shown below. Intermediate(-)-VIIIb is the preferred enantiomer. ##STR12##

The resolved enantiomer is esterified on the 3-carboxyl group forfurther chemical modification. The preferred ester is the ethyl ester.Suitable esterification conditions include the reaction of intermediateVIII (R⁶ is hydrogen) with an akylating reagent in the presence of abase. Suitable akylating reagents for the present transformation includeethyl iodide, ethyl bromide, ethyl chloride, and diethyl sulfate. Thebase is selected from the group consisting of triethylamine,N,N-diisopropylethylamine, pyridine, collidine, sodium bicarbonate, andsodium carbonate. Suitable solvents for the esterification are polarorganic solvents, such as dimethylformamide and acetonitrile. Thisesterification is preferably carried out using ethyl bromide andtriethylamine in acetonitrile at the reflux temperature of the solventfor a period of about one to two hours.

The compounds of the present invention are chemically synthesized fromcommon intermediate VIII by a number of different routes. When thesynthesis begins with racemic intermediate VIII, the products aregenerally racemic mixtures. However, when the synthesis begins withintermediate (-)-VIIIb, the product is a single enantiomer. The specificsynthetic steps of the routes described herein may be combined in otherways to prepare the formula I compounds. The following discussion is notintended to be limiting to the scope of the present invention, andshould not be so construed.

The formula I compounds wherein R³ is a tetrazole group are prepared asoutlined in Scheme II. ##STR13##

Generally, intermediate VIII is reacted with a Wittig reagent to prepareunsaturated intermediate IX. This intermediate is stereoselectivelyconverted to intermediate X by hydroboration and then oxidation.Hydroxymethyl intermediate X is then oxidized to 6-formyl intermediateXI. The 6-formyl group is then converted to a nitrile through anintermediate oxime. The 6-cyano intermediate XII is then converted to aformula I compound wherein R³ is a tetrazole group.

More specifically, intermediate VIII is reacted with a Wittig reagent,such as methyltriphenylphosphonium bromide, to produce intermediate IX.This reaction is generally accomplished by treating the phosphonium saltwith a strong base, such as bis(trimethylsilyl)amide, to generate anylid. This ylid is then reacted in a polar organic solvent, such as drytetrahydrofuran, with VIII to provide the unsaturated intermediate IX.This reaction is generally carried out at a temperature of about -10° C.to about 10° C., preferably at 0° C. When a slight molar excess ofphosphonium salt is employed, the react ion is generally complete inabout one hour.

Intermediate IX is then converted stereoselectively to intermediate X.The preferred method of accomplishing this conversion is hydroborationfollowed by oxidation. A suitable reagent for the hydroboration isborane-methyl sulfide. This hydroboration is generally carried out in apolar organic solvent, such as tetrahydrofuran, at a temperature ofabout -10° C. to about room temperature, preferably at about 0° C. Thereaction is generally complete after a period of about 2 to about 4hours. The product from the hydroboration is then oxidized tointermediate X. A suitable oxidizing agent for this transformation ishydrogen peroxide. The oxidation is generally accomplished by treatingthe hydroboration reaction mixture with hydrogen peroxide and base, suchas sodium hydroxide, and stirring the resulting mixture at a temperatureof about 0° C. to about room temperature, preferably at roomtemperature. The reaction is generally complete after a period of aboutone to about two hours.

The hydroxy intermediate X is then converted to aldehyde intermediateXI. The hydroxyl group is oxidized to the aldehyde with oxidizingreagents and methods which are well known in the chemical arts, such asthe Swern oxidant or other dimethylsulfoxide (DMSO) based reagents.Mancuso, Huang, and Swern, J. Org. Chem., 43, 2480-2482 (1978); Epsteinand Sweat, Chem. Rev., 67, 247-260 (1967); and Smith, Leenay, Lin,Nelson, and Ball, Tetr. Lett., 29, 49-52 (1988). One such reagent is acombination of oxalyl chloride and dimethylsulfoxide. Generally,dimethylsulfoxide (DMSO) and oxalyl chloride are combined in an organicsolvent, such as methylene chloride, at about -78° C. to form theoxidizing agent. After about five to about fifteen minutes, a solutionof the alcohol intermediate is added to the cold oxidizing agentsolution. To prevent racemization of the C-6 hydrogen, this mixture isthen treated with N,N-diisopropylethylamine (Hunig's base), and theresulting reaction mixture cooled to about -78° C. to about -50° C. Thereaction is quenched by the addition of a saturated ammonium chloridesolution.

Intermediate XI is then converted to intermediate XII. A preferredmethod of accomplishing this conversion is formation of thecorresponding oxime followed by dehydration. A suitable reagent for theoximation is hydroxylamine hydrochloride. This oximation is generallycarried out in a polar organic solvent, such as methanol, ethanol, ormethylene chloride, or a mixture of polar organic solvents, such as amixture of methylene chloride and methanol. The reaction is also carriedout in the presence of an amine base, such as pyridine,N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, orcollidine. This oximation is also generally carried out at a temperatureof about 25° C. to about the reflux temperature of the solvent,preferably at room temperature. The reaction is generally complete aftera period of about 30 minutes to about 2 hours. The product fromoximation is then dehydrated to intermediate XII. A suitable dehydratingagent for this transformation is phenylphosphonic dichloride, tosylchloride, mesyl chloride, and phosphorous oxychloride. The dehydrationis generally accomplished by treating the oxime with the dehydratingagent in the presence of an amine base. This dehydration is generallycarried out in a polar organic solvent, such as methylene chloride, at atemperature of about 0° C. to about room temperature, preferably at 0°C. The reaction is generally complete after period of about 18 to about24 hours.

Intermediate XII is converted to tetrazole intermediate XIII bytreatment with tributyltin azide. The nitrile intermediate is reactedwith tributyltin azide at a temperature of about 50° C. to about 120°C., preferably at a temperature of about 80° C. The reaction isgenerally complete after a period of about 24 hours to about seven days.The product of this reaction may be isolated, but is preferablyhydrolyzed directly to a compound of formula I wherein R¹ and R² arehydrogen. This hydrolysis is conducted in 6N hydrochloride acid at atemperature of about 100° C. for a period of about 2 to about 24 hours,to produce a compound of formula I wherein R³ is tetrazole.

The formula I compound wherein R³ is a hydroxyisoxazole group areprepared as shown in Scheme III. ##STR14##

Generally, 6-keto intermediate VIII is converted to the 6-formylintermediate XI as described above. This 6-formyl intermediate XI isconverted to dibromoolefin intermediate XIV and then to ethynylintermediate XV according to the procedure described by Corey and Fuchs.Corey and Fuchs, Tetra. Lett., 36, 3769-3772 (1972). The ethynylintermediate XV is modified using standard techniques and converted to ahydroxyisoxazole group to prepare the formula I compounds.

More specifically, 6-formyl intermediate XI is treated with a mixture oftriphenylphosphine and carbontetrabromide to produce dibromoolefinintermediate XIV. The reaction is generally carried out in methylenechloride at a temperature of about 0° C. for a period of about 5 minutesto about 1 hour. Alternatively, a mixture of zinc dust,triphenylphosphine, and carbontetrabromide in methylene chloride isallowed to react at room temperature for about 24 to about 30 hours, andthen treated with the 6-formyl intermediate. The second reaction iscarried out at a temperature of about 20° C. to about 30° C. for aperiod of about 1 to about 2 hours.

Dibromoolefin intermediate XIV is then converted to ethynyl intermediateXV. Treatment of the dibromoolefin intermediate with about twoequivalents of n-butyllithium produces the lithium acetylide, XV,wherein R⁷ is lithium. This transformation is typically carried in apolar organic solvent, such as tetrahydrafuran, at a temperature ofabout -78° C. to about 25° C. The lithium acetylide is reacted withelectrophiles, such as C₁ -C₄ alkyl halides, phenyl halides, orN-halosuccinimides, to prepare the intermediate compounds wherein R⁷ isa R⁴ group as defined previously. In a typical example, the lithiumacetylide is treated with iodomethane at a temperature of about -78° C.to about -60° C. to prepare intermediate XV wherein R⁷ is methyl.

Acetylenic intermediate XV is then converted to a hydroxyisoxazoleintermediate XVI. Intermediate XV is reacted with dibromoformaldoxime toproduce a cycloadduct. This reaction is carried out at a temperature ofabout 15° C. to about 50° C., preferably at room temperature. A suitablesolvent for this reaction is ethyl acetate. The cycloadduct, a3-bromoisoxazole, is then treated with aqueous base to hydrolyze thebromo group. Suitable aqueous bases include sodium hydroxide andpotassium hydroxide; potassium hydroxide is preferred. This reaction iscarried out in a water miscible organic solvent, such as methanol. Thereaction is preferably carried out at the reflux temperature of thesolvent mixture.

The formula I compounds wherein R¹ is acyl are prepared by the reactionof a formula I compound wherein R¹ is hydrogen with an activated esterof the desired acyl group. The term activated ester means an ester whichrenders the carboxyl function of the acylating group reactive tocoupling with the amino group of the decahydroisoquinoline ring. Thepreferred activated ester is the 2,4,5-trichlorophenyl ester. Thereaction is carried out in a polar organic solvent, such asdimethylformamide or tetrahydrofuran, at a temperature of about 25° C.to 110° C. for a period of about 1 to about 5 hours. The reaction forthe formation of acyl derivatives of the formula I compounds ispreferably carried out at a temperature of about 30° C. to about 70° C.for a period of about 2 to about 4 hours.

The formula I compounds wherein R¹ is a C₁ -C₁₀ alkyl or arylalkyl groupare prepared using standard synthetic methods. One method for thesynthesis of these compounds is the reaction of the aldehydecorresponding to the C₁ -C₁₀ alkyl or arylalkyl group with a formula Icompound wherein R¹ is hydrogen in the presence of a reducing agent.Suitable reducing agents include sodium cyanoborohydride and formicacid. This reaction is typically carried out in a polar organic solvent,such as methanol or ethyl acetate, at room temperature. The formula Icompounds wherein R¹ is alkoxycarbonyl or aryloxycarbonyl are preparedusing procedures similar to that described above for the synthesis ofintermediate VI.

The formula I compounds wherein R² is C₁ -C₆ -alkyl, substituted alkyl,cycloalkyl, or arylalkyl are prepared from the corresponding compoundswherein R² is hydrogen. These compounds are generally prepared usingstandard synthetic methodologies. In a typical example, the formula Icompound, wherein R¹ is hydrogen, is reacted with an aryl-alkyl halide,such as benzyl bromide, in the presence of a base to produce thearylalkyl ester derivative. Suitable bases for this transformationinclude tertiary amines, such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, and collidine, and sodiumcarbonate. The reaction is typically run in an organic solvent, such astetrahydrofuran, acetonitrile, and dimethylformamide. Alternatively, theformula I compound, wherein R¹ is hydrogen, can be reacted with asubstituted alkyl, cycloalkyl, or arylalkyl alcohol in the presence ofacid to produce the corresponding ester. Typically, this reaction iscarried out with an excess of the alcohol in the presence ofconcentrated sulfuric acid.

The formula I compounds of the present invention are excitatory aminoacid antagonists. In particular, these compounds are antagonists of theAMPA and NMDA subtypes of excitatory amino acid receptors. Therefore,another aspect of the present invention is a method of blocking the AMPAor NMDA excitatory amino acid receptors in mammals which comprisesadministering to a mammal requiring decreased excitatory amino acidneurotransmission a pharmaceutically-effective amount of a compound offormula I.

The term "pharmaceutically-effective amount" is used herein to representan amount of the compound of the invention which is capable of blockingthe AMPA or NMDA excitatory amino acid receptors. The particular dose ofcompound administered according to this invention will of course bedetermined by the particular circumstances surrounding the case,including the compound administered, the route of administration, theparticular condition being treated, and similar considerations. Thecompounds can be administered by a variety of routes including the oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, orintranasal routes. Alternatively, the compounds may be administered bycontinuous infusion. A typical daily dose will contain from about 0.01mg/kg to about 30 mg/kg of the active compound of this invention.Preferred daily doses will be about 0.05 mg/kg to about 24 mg/kg, morepreferably about 0.1 to about 20 mg/kg.

A variety of physiological functions have been shown to be subject toinfluence by excessive or inappropriate stimulation of excitatory aminoacid neurotransmission. The formula I compounds of the present inventionare believed to have the ability to treat a variety of neurologicaldisorders in mammals associated with this condition which include acuteneurological disorders such as cerebral deficits subsequent to cardiacbypass surgery and grafting, stroke, cerebral ischemia, spinal cordtrauma, head trauma, perinatal hypoxia, cardiac arrest and hypoglyemicneuronal damage. The formula I compounds are believed to have theability to treat a variety of chronic neurological disorders such asAlzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis,AIDS-induced dementia, ocular damage and retinopathy, and idiopathic anddrug-induced Parkinson's Disease. The present invention also providesmethods for treating these disorders which comprise administering to apatient in need thereof an effective amount of a compound of formula I.

The formula I compounds of the present invention are also believed tohave the ability to treat a variety of other neurological disorders inmammals that are associated with glutamate dysfunction includingmuscular spasms, convulsions, migraine headaches, urinary incontinence,psychosis, opiate tolerance and withdrawal, anxiety, emesis, brainedema, chronic pain, and tardive dyskinesia. The formula I compounds arealso useful as analgesic agents. Therefore, the present invention alsoprovides methods for treating these disorders which compriseadministering to a patient in need thereof an effective amount of acompound of formula I.

Experiments were performed to demonstrate the inhibitory activity of theformula I compounds of this invention at theα-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) andN-methyl-D-aspartate (NMDA) subtypes of excitatory amino acid receptors.The formula I compounds were tested for their ability to inhibit NMDA,AMPA, and kainic acid receptor binding to rat membranes in a radioligandbinding assay using [³ H]CGS19755, [³ H]AMPA, and [³ H]KA. For allradioligand binding assays, male Sprague-Dawley rats were used.Displacement of the specific binding [³ H]CGS19755 (10 nM) toTriton-X-treated synaptosomal membranes of rat forebrain was used todetermine NMDA receptor affinity. Non-specific binding was determinedusing 10 μM L-glutamate. Samples were incubated in an ice-bath for 30minutes, and bound ligand was separated from the free ligand by rapidfiltration through WHATMAN GF/B glass fiber filters. Murphy et al,British J. Pharmacol., 95, 932-938 (1988). Kainate binding was performedusing washed synaptosomal membranes from the rat forebrain as describedby Simon et al. Simon et al, J. Neurochem., 26, 141-147 (1976).Tritiated kainate (5 nM) was added to 50 mM Tris-HCl buffer (pH 7.4 at4° C.) containing 200-300 μg/ml of tissue protein. Samples wereincubated for 30 minutes in an ice-bath, then rapidly filtered using aBrandel cell harvester and WHATMAN GF/C filters. Filters were washedtwice with 3 ml of cold buffer. Non-specific binding was determinedusing 100 μM non-labeled kainate. The binding of [³ H]AMPA (5 nM) wasconducted with crude membranes of rat forebrain in the presence of 100mM KSCN as described by Nielson et al. Nielson et al, Eur. J. Med. Chem.Chim. Ther., 21, 433-437 (1986). Non-specific binding was determinedwith 10 μM non-labeled AMPA. The concentration of the formula I compoundthat inhibited 50% binding (IC₅₀, mean ± standard error, n=3) ascalculated by linear regression of displacement data transformed to theHill equation as described by Bennett. Bennett, NeurotransmitterReceptor Binding, 57-90 (1978). The results of the radioligand bindingassays are shown in Table I.

                                      TABLE I                                     __________________________________________________________________________    Receptor Binding of Formula I Compounds                                       Compound                 IC.sub.50 (μM).sup.a                              No.                                                                              Structure             NMDA  AMPA   KA                                      __________________________________________________________________________    1.sup.b                                                                           ##STR15##            1.56 ± 0.23                                                                      12.84 ± 0.27                                                                      31.84 ± 2.31                         2.sup.c                                                                           ##STR16##            0.96.sup.d                                                                           5.72 ± 0.89                                                                      21.0.sup.d                              __________________________________________________________________________     .sup.a Mean ± standard error (n = 3), unless otherwise indicated.           .sup.b The compound was tested as a racemic mixture with the relative        stereochemistry as shown.                                                     .sup.c The compound was tested as a single enantiomer with the absolute       stereochemistry as shown.                                                     .sup.d The data is the result of a single experiment.                    

The depolarization of rat cortical edges was used to test theselectivity and potency of the formula I compounds as AMPA and NMDAantagonists using a technique similar to that described by Harrison andSimmonds. Harrison and Simmonds, Bri. J. Pharmacol., 84, 381-391 (1984).Generally, 4-ml aliquots of NMDA (40 μM) AMPA (40 μM), and kainate (10μM) were superfused (2 ml/min.) on the grey matter at intervals of 15-20minutes until stable responses were attained. The tissue was thenexposed for 15 minutes to various concentrations of the formula Icompounds before retesting the agonists. The IC₅₀ values were calculatedfrom linear regression of log dose-response curves, each point the meanof at least three observations on separate slices from more than oneanimal. The results of these tests are shown in Table II.

                                      TABLE II                                    __________________________________________________________________________    Antagonism of Cortical Wedge Depolarization by Formula I Compounds            Compound                 IC.sub.50 (μM).sup.a                              No.                                                                              Structure             NMDA  AMPA   KA                                      __________________________________________________________________________    1.sup.b                                                                           ##STR17##            7.5 ± 0.7                                                                        40.9 ± 5.2                                                                        >100                                    2.sup.c                                                                           ##STR18##            4.1 ± 0.3                                                                        13.2 ± 2.4                                                                        >100                                    __________________________________________________________________________     .sup.a Mean ± standard error (n = 3).                                      .sup.b The compound was tested as a racemic mixture with the relative         stereochemistry as shown.                                                     .sup.c The compound was tested as a single enantiomer with the absolute       stereochemistry as shown.                                                

The data shows that the formula I compounds possess selective affinityfor the AMPA and the NMDA ionotropic glutamate receptors. Theradioligand binding assay is the preferred assay for discriminatingbetween AMPA and KA selectivity. The formula I compounds, in particularcompound 2, displaced ³ H-AMPA and [³ H]CGS19755 with IC₅₀ values lessthan 10 μM (Table I). The cortical wedge assay is the preferred assayfor discriminating between AMPA and NMDA selectivity. This assay alsodistinguishes between agonist and antagonist activity. The formula Icompounds, in particular compound 2, are shown to between AMPA and NMDAreceptor antagonists (Table II).

The compounds of the present invention are preferably formulated priorto administration. Therefore, another aspect of the present invention isa pharmaceutical formulation comprising a compound of formula I and apharmaceutically-acceptable carrier, diluent, or excipient.

The present pharmaceutical formulations are prepared by known proceduresusing well-known and readily available ingredients. In making thecompositions of the present invention, the active ingredient willusually be mixed with a carrier, or diluted by a carrier, or enclosedwithin a carrier which may be in the form of a capsule, sachet, paper,or other container, when the carrier serves as a diluent, it may be asolid, semi-solid, or liquid material which acts as a vehicle,excipient, or medium for the active ingredient. The compositions can bein the form of tablets, pills, powders, lozenges, sachet, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointmentscontaining, for example up to 10% by weight of active compound, soft andhard gelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc,magnesium sterate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents, or flavoring agents.Compositions of the inventions may be formulated so as to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 5 to about 5000 mg, more preferably about25 to about 3000 mg of the active ingredient. The most preferred unitdosage form contains about 100 to about 2000 mg of active ingredient.The term "unit dosage form" refers to a physically discrete unitsuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical carrier. The following formulation examples areillustrative only and are not intended to limit the scope of theinvention in any way.

FORMULATION 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                           Quantity                                                                      (mg/capsule)                                               ______________________________________                                        6-(1(2)H-Tetrazole-5-yl)-                                                                          250                                                      decahydroisoquinoline-                                                        3-carboxylic acid                                                             Starch, dried        200                                                      Magnesium stearate   10                                                       Total                460     mg                                               ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

FORMULATION 2

A tablet is prepared using the ingredients below:

    ______________________________________                                                             Quantity                                                                      (mg/tablet)                                              ______________________________________                                        6-(1(2)H-Tetrazole-5-yl)decahydro-                                                                   250                                                    isoquinoline-3-carboxylic acid                                                Cellulose, microcrystalline                                                                          400                                                    Silicon dioxide, fumed 10                                                     Stearic acid           5                                                      Total                  665     mg                                             ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg.

FORMULATION 3

An aerosol solution is prepared containing the following components:

    ______________________________________                                                            Weight %                                                  ______________________________________                                        6-(3-Hydroxyisoxazol-5-yl)decahydro-                                                                0.25                                                    isoquinoline-3-carboxylic acid                                                Ethanol               29.75                                                   Propellant 22         70.00                                                   (chlorodifluoromethane)                                                       Total                 100.00                                                  ______________________________________                                    

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to -30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

FORMULATION 4

Tablets each containing 60 mg of active ingredient are made as follows:

    ______________________________________                                        6-(3-Hydroxyisoxazol-5-yl)decahydro-                                                                 60 mg                                                  isoquinoline-3-carboxylic acid                                                Starch                 45 mg                                                  Microcrystalline cellulose                                                                           35 mg                                                  Polyvinylpyrrolidone   4 mg                                                   Sodium carboxymethyl starch                                                                          4.5 mg                                                 Magnesium stearate     0.5 mg                                                 Talc                   1 mg                                                   Total                  150 mg                                                 ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

FORMULATION 5

Capsules each containing 80 mg medicament are made as follows:

    ______________________________________                                        6-(1(2)H-Tetrazole-5-yl)-                                                                             80 mg                                                 decahydroisoquinoline-                                                        3-carboxylic acid                                                             Starch                  59 mg                                                 Microcrystalline cellulose                                                                            59 mg                                                 Magnesium stearate      2 mg                                                  Total                   200 mg                                                ______________________________________                                    

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 sieve, and filled into hard gelatincapsules in 200 mg quantities.

FORMULATION 6

Suppositories each containing 225 mg of active ingredient may be made asfollows:

    ______________________________________                                        6-(3-Hydroxyisoxazol-5-yl)decahydro-                                                                   225 mg                                               isoquinoline-3-carboxylic acid                                                Saturated fatty acid glycerides                                                                        2,000 mg                                             Total                    2,225 mg                                             ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

FORMULATION 7

Suspensions each containing 50 mg of medicament per 5 ml dose are madeas follows:

    ______________________________________                                        6-(3-Hydroxyisoxazol-5-yl)decahydro-                                                                   50     mg                                            isoquinoline-3-carboxylic acid                                                Sodium carboxymethyl cellulose                                                                         50     mg                                            Syrup                    1.25   ml                                            Benzoic acid solution    0.10   ml                                            Flavor                          q.v.                                          Color                           q.v.                                          Purified water to total  5      ml                                            ______________________________________                                    

The medicament is passed through a No 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

FORMULATION 8

An intravenous formulation may be prepared as follows:

    ______________________________________                                        6-(1(2)H-Tetrazole-5-yl)-                                                                            100    mg                                              decahydroisoquinoline-                                                        3-carboxylic acid                                                             Mannitol               100    mg                                              5 N Sodium hydroxide   200    μl                                           Purified water to total                                                                              5      ml                                              ______________________________________                                    

The following Examples further illustrate the compounds of the presentinvention and the methods for their synthesis. The Examples are notintended to be limiting to the scope of the invention in any respect,and should not be so construed. All experiments were run under apositive pressure of dry nitrogen. Tetrahydrofuran (THF) was distilledfrom sodium prior to use. All other solvents and reagents were used asobtained. Proton nuclear magnetic resonance (¹ H NMR) spectra wereobtained on a GE QE-300 spectrometer at 300.15 MHz or a Bruker AM-500spectrometer at 500 MHz. Where indicated, a small amount of 40% aqueousKOD was added to aid solution of NMR samples run in D₂ O.Chromatographic separation on WATERS Prep 500 LC was generally carriedout using a linear gradient of hexane to the solvent indicated in thetext. The reactions were generally monitored for completion using thinlayer chromatography (TLC). Thin layer chromatography was performedusing E. Merck Kieselgel 60 F₂₅₄ plates, 5 cm×10 cm, 0.25 mm thickness.Spots were detected using a combination of UV and chemical detection[plates dipped in a ceric ammonium molybdate solution (75 g of ammoniummolybdate and 4 g of cerium (IV) sulfate in 500 mL of 10% aqueoussulfuric acid) and then heated on a hot plate]. Flash chromatography wasperformed as described by Still, et al. Still, Kahn, and Mitra, J. Org.Chem., 43, 2923 (1978). Elemental analyses for carbon, hydrogen, andnitrogen were determined on a Control Equipment Corporation 440Elemental Analyzer. Melting points were determined in open glasscapillaries on a Gallenkamp hot air bath melting point apparatus, andare uncorrected.

PREPARATION 1 6-Hydroxytetrahydroisoquinoline-3-carboxylic Acid (V)

A slurry of d,l-m-tyrosine (1.91 kg) in dilute hydrochloric acid (76 mlof conc. HCl, 11.5L of water) was heated to 55°-60° C., and treated withformaldehyde (1.18L). Heating at 55°-70° C. was continued for 2 hours,then the reaction mixture was cooled to 3°-10° C. for 2 hours. Theresulting mixture was filtered, and the filtrate washed with deionizedwater and acetone. The filter cake was dried in a vacuum oven at 55°-60°C. to give 1.88 kg of the title compound.

¹ H NMR (D₂ O/KOD): δ 6.75 (d, 1H), 6.5 (d, 1H), 6.30 (s, 1H), 3.77 (d,1H), 3.69 (d, 1H), 3.26 dd, 1H), 2.79 (dd, 1H), 2.60 (dd, 1H).

Analysis calculated for C₁₀ H₁₁ NO₃.0.85 H₂ O: C, 57.60; H, 6.13; N6.71. Found: C, 57.70; H, 6.43; N, 6.69.

PREPARATION 2 Ethyl6-Hydroxy-2-methoxycarbonyltetrahydroisoquinoline-3-carboxylate (VI)

To a mixture of the compound from Preparation 1 (91.2 g) in ethanol (455ml) was added concentrated sulfuric acid (27.5 ml) over a period of twominutes. After the initial exothermic reaction, the solution was heatedat reflux for 16 hours. The resulting solution was cooled in an icewater bath, and a solution of potassium carbonate (130.5 g) in water(130.5 ml) was added. Methyl chloroformate (36.5 ml) was added to thissolution at a rate such that the pH was greater than 6.9 and thetemperature was less than 14° C. After an additional two hours, thereaction mixture was partitioned between ethyl acetate (250 ml) andwater (500 ml). The layers were separated and aqueous layer extractedwith two portions of ethyl (100 ml each). The organic layers werecombined and concentrated in vacuo to give a solid residue. The residuewas crystallized by dissolving in refluxing ethanol (180 ml), dilutingthe ethanol solution with water (360 ml), and stirring the resultingmixture at 4° C. for 24 hours. The crystalline solid was collected byfiltration and dried in a vacuum oven (40° C., 23 hours) to give 93.9 gof the title compound.

¹ H NMR (CDCl₃): δ 6.95 (m, 1H), 6.67 (d, 1H), 6.61 (s, 1H), 5.76 (s,1H), 5.06 and 4.85 (m, 1].), 4.65 (dd, 1H), 4.48 (d, 1h), 4.05 (m, 2H),3.78 and 3.73 (s, 3H), 3.11 (m, 2H), 1.11 (t, 3H) (doubling due to amiderotamers).

Analysis calculated for C₁₄ H₁₇ NO₅ : C, 60.21; H, 6.14; N, 5.02. Found:C, 60.49; H, 6.24; N, 4.98.

PREPARATION 3 Ethyl2-Methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate (VIII)

Alternative 1.

A. Preparation of Ethyl6-Hydroxy-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate (VII)

To a mixture of 3% rhodium on alumina (6.9 g) in ethyl acetate (350 ml)was added the compound from Preparation 2 (69.03 g). After sealing thevessel, the nitrogen atmosphere was replaced with hydrogen. The reactionwas heated to 85° C. at a pressure of 100 psi for 23 hours. Anadditional portion of rhodium on alumina (1.4 g) was added and theheating resumed at elevated pressure for an additional two hours. Thecatalyst was removed by filtration, and the filtrate containing thetitle compound was used in the next step.

B. Preparation of Ethyl2-Methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate (VIII)

To a solution of ruthenium(III) chloride (69 mg) in water (9.8 ml) wasadded the filtrate from Preparation 3A. The resulting two-phase mixturewas cooled in an ice-water bath and treated with a solution of periodicacid (69 g) in water (26.9 ml). The periodic acid solution was added ata rate such that the temperature of the reaction mixture was less than7.8° C. After the addition of the periodic acid, the ice bath wasremoved and the reaction mixture was allowed to warm to roomtemperature. After 11/4 hours, the aqueous phase was removed and theorganic phase washed with two portions of water (50 ml each). Theorganic phase was concentrated to dryness in vacuo to give 67.7 g of thetitle compound as an oil.

Alternative 2.

Preparation of Ethyl6-Hydroxy-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate (VII) andEthyl 2-Methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate (VIII)

A mixture of 3% rhodium on carbon (1.0 kg) and the compound prepared asdescribed in Preparation 2 (13.2 kg) in ethyl acetate (67 liters) washydrogenated at a hydrogen pressure of 100 psi at about 85° C. After 23hours, the reaction mixture was cooled to room temperature and thecatalyst removed by filtration. The catalyst cake was washed withadditional ethyl acetate (10 liters), and the ethyl acetate filtratescombined.

A sample of the ethyl acetate solution from the preceding paragraph wasconcentrated in vacuo to give 3.295 g of colorless oil, which was amixture of C-6 ketone and C-6 alcohols. This mixture was separated bysilica-gel flash chromatography, eluting with a linear gradient ofmethylene chloride to methylene chloride/ethyl acetate (9:1) followed byethyl acetate, to give two products. The fractions containing the firstproduct were combined and concentrated in vacuo to give 1.18 g ofcompound VIII. The fractions containing the second product were combinedand concentrated in vacuo to give 1.36 g of compound VII.

PREPARATION 4 (3S,4aS,8aR)-(-) Ethyl2-Methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate ((-)-VIIIb)A. Preparation of2-Methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylic Acid

The compound from Preparation 3B (1.913 kg) was added to a 21% sodiumethoxide solution (509 g) in ethanol (8L). The resulting solution washeated to reflux for a period of six hours, and then allowed to cool toroom temperature over a period of 24 hours. This solution was treatedwith 5N sodium hydroxide solution (2.4L) and allowed to remain at atemperature of about 25° C. to about 40° C. for a period of two hours.The reaction mixture was concentrated in vacuo to remove the ethanol.The residue was extracted with two portions of t-butylmethyl ether (5Leach), and the pH of the aqueous phase was adjusted to about 1.5 toabout 2.5 by adding concentrated hydrochloric acid (1.7L). The titlecompound was extracted from the aqueous solution with ethyl acetate(4×3L). The combined ethyl acetate extracts were treated with FLORISIL(960 g) and sodium sulfate (960 g). The ethyl acetate filtratecontaining the title compound was used in the next step without furtherpurification.

B. Preparation of(3S,4aS,8aR)-(-)-2-Methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylateα-methylbenzylamine salt

To the ethyl acetate filtrate from Preparation 4A was addedR-(+)-α-methylbenzylamine at a temperature of about 25° C. to about 30°C. over a period of one hour. The resultant slurry was allowed to remainat room temperature for a period of 24 hours, and then the precipitatewas collected by filtration. The solid material was rinsed with severalportions of ethyl acetate until the rinse was colorless. The filter cakewas dried in a vacuum oven at a temperature of about 45°-50° C. Thismaterial was reslurried in 10 volumes of ethyl acetate at a temperatureof about 45° C. to about 50° C. for about four hours, the solution wasallowed to cool to ambient temperature, and the solid material removedby filtration. The solids were dried in vacuo at about 45° C. to about50° C. to give 1.092 kg of the title compound.

[α]_(D) =-57.0° (c=1, H₂ O).

Analysis calculated for C₂₀ H₂₈ N₂ O₅ : C, 63.81; H, 7.50; N, 7.44.Found: C, 63.87; H, 7.33; N, 7.33.

C. Preparation of (3S,4aS,8aR)-(-) Ethyl2-Methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate ((-)-VIIIb)

A mixture of the compound from Preparation 4B (50 g) and acetonitrile(250 ml), was treated with triethylamine (26.8 g) and ethyl bromide (73g). The resulting mixture was heated to reflux causing dissolution ofthe reactants. After about one to about two hours, the reaction wasallowed to cool to room temperature and concentrated in vacuo. Theresidue was treated with ethyl acetate (250 ml). The resulting mixturewas filtered and the solids rinsed with additional ethyl acetate. Thefiltrate was extracted with 3N hydrochloric acid, dried over MgSO₄,filtered, and concentrated in vacuo to give 34.9 g of the titlecompound.

[α]_(D) =-51.3° (c=1, CH₂ Cl₂)

Analysis calculated for C₁₄ H₂₁ NO₅ : C, 59.35; H, 7.47; N, 4.94. Found:C, 59.11; H, 7.20; N, 4.90.

D. Preparation of (3R4aR8aS)-(+) Ethyl2-Methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate ((+)-VIIIb)

The title compound was prepared from the racemic mixture fromPreparation 4A using the procedures described in Preparation 4B and 4Cwith S-α-methylbenzylamine.

PREPARATION 5 (3SR,4aSR,8ARS) Ethyl2-Methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate ((±)-VIIIb)A. Preparation of Ethyl6-Hydroxy-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate

A mixture of the compound from Preparation 2 (158.9 g) and 5% rutheniumon alumina (80 g) in ethanol (1760 ml) was hydrogenated at a pressure of2000 psi. After 16 hours at about 180° C., the cooled reaction mixturewas filtered through CELITE, and the filtrate concentrate in vacuo. Theresidue was diluted with ethyl acetate. This mixture was filteredthrough CELITE, and concentrate in vacuo to give 156.7 g of the titlecompound.

B. Preparation of Ethyl2-Methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate (VIII)

A solution of the compound from Preparation 5A (156.7 g) in methylenechloride (300 ml) was added to a mixture of pyridinium chlorochromate(260.5 g) and added 4 Å molecular sieves in methylene chloride (1400ml), which was allowed to stir one hour prior to the addition of thealcohol. After two hours, the reaction mixture was diluted with etherand filtered through a layer ea of CELITE and silica gel. The solidswere washed with ether, and the combined ether solutions concentrated invacuo. The residue was dissolved in ether, filtered through CELITE andsilica gel, and the filtrate concentrated in vacuo to give 128.8 g of amixture of VIIIa and VIIIb (VIIIa:VIIIb=78:22).

C. Preparation of (3SR,4aSR,8aRS)-(±) Ethyl2-Methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate (VIIIb)

A solution of the mixture from Preparation 5B (128.8 g) in ethanol (1000ml) was treated with a solution of sodium hydride (1.82 g) in ethanol(100 ml), and the resulting mixture heated to reflux. After 11/2 hours,the mixture was allowed to cool to room temperature and concentrated invacuo. The residue was dissolved in methylene chloride/ether (1:1), andwashed 10% aqueous sodium bisulfate. The aqueous phase was extractedwith ether, the organic phases combined, dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified bysilica-gel chromatography on a WATERS PREP 500 LC, eluting with a lineargradient of hexane to 25% ethyl acetate/hexane, to give 106.9 g of amixture of VIIIa and VIIIb (VIIIa:VIIIb=13:87). Recrystallization ofthis mixture from ether gave 67.0 g of the title compound. Melting point78°-79° C.

    ______________________________________                                        .sup.1 H NMR (DMSO) δ: 4.76(d, 1H), 4.124(q, 2H), 3.80(d,               1H), 3.61(s, 3H), 3.21(bd, 1H), 2.65(dd, 1H), 2.43(dt,                        1H), 2.19(m, 1H), 2.14(m, 2H), 1.98(ddd, 1H), 1.85(m,                         1H), 1.75(m, 1H), 1.65(dt, 1H), 1.20(t, 3H).                                  ______________________________________                                    

Analysis calculated for C₁₄ H₂₁ NO₅ : C 59.35; H, 7.47; N, 4.94. Found:C, 59.62; H, 7.61; N, 4.97.

EXAMPLE 1(3SR,4aRS,6SR,8aRS)-6-(1(2)H-Tetrazole-5-yl)decahydroisoquinoline-3-carboxylicAcid A. Preparation of Ethyl6-Methylidine-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate

Methyltriphenylphosphonium bromide (7.3 g) was added to tetrahydrofuran(800 ml). This mixture was stirred at room temperature for 15 minutes,then filtered. The solid was dried in vacuo at about 50° C. for 30minutes. The residue was suspended in tetrahydrofuran (220 ml) and theresulting mixture cooled to 0° C. The cold mixture was treated with a 1Msolution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (213.6ml). After 15 minutes, the resulting solution was added to a cold (0°C.) solution of the racemic compound from Preparation 5C (43.23 g) intetrahydrofuran (320 ml) until a pale yellow color persisted. Thereaction mixture was treated with water (250 ml) and ether (500 ml), andthe phases separated. The organic phase was extracted with water (10ml), and the aqueous phase extracted with ether (2 times). The organicphases were combined, dried, and concentrated in vacuo. The residue wassuspended in 25% ethyl acetate/hexane and the resulting mixture stirredat room temperature. After one hour, the mixture was filtered and thesolids rinsed with 25% ethyl acetate/hexane. The filtrate wasconcentrated in vacuo. The residue was purified by silica-gel flashchromatography, eluting with 25% ethyl acetate/hexane, to give 40.67 gof the title compound.

B. Preparation of (3SR,4aRS,6SR,8aRS) Ethyl6-Hydroxymethyl-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate

A cold (0° C.) solution of the compound from Example 1A (40.67 g) intetrahydrofuran (285 ml) was treated with a 10M solution ofborane-methyl sulfide (9.7 ml). After two hours at 0° C., the reactionwas allowed to warm to room temperature. After an additional 21/2 hours,the reaction mixture was cooled to 0° C. and treated ethanol (25 ml), 3Nsodium hydroxide (200 ml), and 30% hydrogen peroxide (200 ml). After 30minutes at 0° C., the reaction mixture was allowed to warm to roomtemperature. After an additional two hours at room temperature, thismixture was extracted with ether (3 times). The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo. The residue was purified by silica-gel chromatography on aWATERS PREP 500 LC, eluting with a gradient of hexane to 60% ethylacetate/hexane, to give 40.36 g of the title compound.

C. Preparation of (3SR,4aRS,6SR,8aRS) Ethyl6-Formyl-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate

A solution of dimethylsulfoxide (22.5 ml) in methylene chloride (250 ml)was cooled to -78° C. and treated with oxalyl chloride (13.3 ml). Afterfive minutes, this cold solution was treated with a solution of thecompound from Example 1B (38.0 g) in methylene chloride (150 ml). Afteran additional 15 minutes, this mixture was treated with triethylamine(88.5 ml). After an additional 45 minutes at -78° C., the reactionmixture was allowed to warm to room temperature and treated with 10%sodium bisulfate (1000 ml) and ether (750 ml). The phases were separatedand the aqueous extracted with ether (2 times). The organic phases werecombined, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was used in the next step without furtherpurification.

D. Preparation of (3SR,4aRS,6RS,8aRS) Ethyl6-cyano-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate

A solution of the compound from example 1C (37.8 g) in methylenechloride (570 ml), methanol (165 ml) and pyridine (20.5 ml) was treatedat room temperature with hydoxylamine hydrochloride (8.83 g). After 30minutes at room temperature, the reaction mixture was concentrated invacuo, then additional methylene chloride (300 ml) was added and themixture again concentrated in vacuo. The residue was dissolved inmethylene chloride (870 ml) and pyridine (20.5 ml), cooled to 0 ° C. andtreated dropwise with phenylphosphonic dichloride (36.0 ml). Afterstirring overnight at room temperature, the reaction mixture wasquenched with saturated aqueous sodium bicarbonate (750 ml), then ether(1000 ml) was added, the phases separated and the organic phase washed10% sodium bisulfate (750 ml). The organic phase was dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waspurified by silica-gel chromatography on a WATERS PREP 2000 LC, loadingin 25% ethyl acetate/toluene and eluting with a gradient of 5 % ethylacetate/hexane to 35% ethyl acetate/hexane, to give 31.6 g of the titlecompound.

E. Preparation of(3SR,4aRS,6RS,8aRS)-6-[2-(1(2)H-Tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylicAcid

The compound from Example 1D (31.6 g) and tributyltin azide (79.2 g) intoluene (30 ml) was heated to 80° C. After 7 days, the mixture wastreated with 6N hydrochloric acid (250 ml) and heated to 100° C. Afterheating about 18 hours, the mixture was allowed to cool to roomtemperature. This mixture was extracted six times with ether (200 ml),and the aqueous phase concentrated in vacuo. The residue was purified byion-exchange chromatography on DOWEX 50X8, eluting with 10%pyridine/water. The fractions containing the title compound werecombined and concentrated in vacuo. The residue was diluted with waterand concentrated in vacuo. This procedure was repeated. The residue wassuspended in 150 ml water, cooled to 0 ° C. for 4 hours, then filteredend the solids washed with acetone and ether. The solid material wasdried in vacuo at 60° C. for about 18 hours, to give 16.4 g of the titlecompound. Melting point 283° C.

Analysis calculated for C₁₁ H₁₇ N₅ O₂.0.55H₂ O: C, 50.58; H, 6.98; N,26.81. Found: C, 50.57; H, 6.75; N, 26.57.

EXAMPLE 2(3S,4aR,6S,8aR)-6-(1(2)H-Tetrazole-5-yl)decahydroisoquinoline-3-carboxylicAcid A. Preparation of (3S,4aR,8aR) Ethyl6-Methylidine-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate Acid

The reaction of methyltriphenylphosphonium bromide (17.6 g), a 1Msolution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (49 ml),and (3S,4aS,8aR)-(-) ethyl2-methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate (10.0 g) asdescribed in Example 1A produced the crude title compound. This materialwas purified by silica-gel flash chromatography, eluting with 25% ethylacetate/hexane, to give 9.25 g of the title compound.

B. Preparation of (3S,4aR,6S,8aR) Ethyl6-Hydroxymethyl-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate

A cold (0° C.) solution of the compound from Example 2A (9.25 g) intetrahydrofuran (65 ml) was treated with a 10M solution of borane-methylsulfide (2.2 ml). After three hours, the reaction solution was treatedwith ethanol (7.5 ml), then 3N sodium hydroxide (22 ml), then 30%hydrogen peroxide (22 ml). After 1 hour at 0° C., this mixture wasextracted with ether (3 times). The organic phases were combined, driedover magnesium sulfate, filtered, and concentrated in vacuo. The residuewas purified by silica-gel chromatography on a WATERS PREP 2000 LC,eluting with a gradient of hexane to 60% ethyl acetate/hexane, to give7.53 g of the title compound.

C. Preparation of (3S,4aR,6S,8aR) Ethyl6-Formyl-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate

A solution of dimethylsulfoxide (1.2 ml) in methylene chloride (14 ml)was cooled to -78° C. and treated with oxalyl chloride (0.7 ml). Afterfive minutes, this cold solution was treated with a solution of thecompound from Example 2B (2.00 g) in methylene chloride (6 ml). After anadditional 15 minutes, this mixture was treated with triethylamine (4.7ml). After an additional 45 minutes at -78° C., the reaction mixture wasallowed to warm to room temperature and treated with 10% sodiumbisulfate (50 ml) and ether (50 ml). The phases were separated and theaqueous extracted with ether (2 times). The organic phase were combined,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was used in the next step without further purification.

D. Preparation of (3S,4aR,6S,8aR) Ethyl6-cyano-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate

A solution of the compound from example 2C (2.00 g) in methylenechloride (30 ml), methanol (9 ml) and pyridine (1.1 ml) was treated atroom temperature with hydoxylamine hydrochloride (0.46 g). After 30minutes at room temperature, the reaction mixture was concentrated invacuo, then additional methylene chloride (30 ml) was added and themixture again concentrated in vacuo. The residue was dissolved inmethylene chloride (43 ml) and pyridine (1.1 ml), cooled to 0 ° C. andtreated dropwise with phenylphosphonic dichloride (1.9 ml). Afterstirring overnight at room temperature, the reaction mixture wasquenched with saturated aqueous sodium bicarbonate (50 ml), then ether(75 ml) was added, the phases separated and the organic phase washedwith 10% sodium bisulfate (50 ml). The organic phase was dried overmagnesium sulfate, filtered, and concentrated in vacuo. This materialwas purified by silica-gel flash chromatography, eluting with 35% ethylacetate/hexane, to give 1.68 g of the title compound.

E. Preparation of (3S,4aR,6S,8aR)-6-[2-(1(2)H-Tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylicAcid

The compound from Example 2D (1.68 g and tributyltin azide (3.68 g) washeated to 80° C. After 7 days, the mixture was treated with 6Nhydrochloric acid (50 ml ) and heated to 100° C. After heating about 18hours, the mixture was allowed to cool to room temperature. This mixturewas extracted six times with ether (20 ml), and the aqueous phaseconcentrated in vacuo. The residue purified by ion-exchangechromatography on DOWEX 50X8, eluting with 10% pyridine/water. Thefractions containing the title compound were combined and concentratedin vacuo. The residue was diluted with water and concentrated in vacuo.This procedure was repeated. The residue treated with acetone, thenheated to reflux for one. The cooled mixture was filtered and the solidmaterial washed with acetone and ether, then dried in vacuo for 18 hoursat 60° C. to give 1.12 g of the title compound. Melting point 244°-247°C.

[a]_(D) =-22.8° (c=1, 1N HCl)

Analysis calculated for C₁₁ H₁₇ N₅ O₂.1.25H₂ O: C, 48.25; H, 7.18; N,25.58. Found: C, 48.16; H 6.75; N, 25.83.

We claim:
 1. A compound of the formula ##STR19## wherein: R¹ ishydrogen, C₁ -C₁₀ alkyl, arylalkyl, alkoxycarbonyl, aryloxycarbonyl, oracyl;R² is hydrogen, C₁ -C₆ alkyl, substituted alkyl, cycloalkyl, orarylalkyl; R³ is a group of the formula ##STR20## R⁴ is hydrogen, C₁ -C₄alkyl, CF₃, phenyl, bromo, iodo, or chloro; or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1 wherein:R¹ ishydrogen, alkoxycarbonyl, or aryloxycarbonyl; R² is hydrogen, C₁ -C₆alkyl, or arylalkyl; R³ is a group of the formula ##STR21## R⁴ ishydrogen, C₁ -C₄ alkyl, CF₃, or phenyl; or a pharmaceutically acceptablesalt thereof.
 3. A compound of claim 2 wherein:R¹ is hydrogen oralkoxycarbonyl; R² is hydrogen or C₁ -C₆ alkyl; or a pharmaceuticallyacceptable salt thereof.
 4. A compound of claim 3 wherein R³ is a groupof the formula ##STR22## or a pharmaceutically acceptable salt thereof.5. A compound of claim 3 wherein:R¹ is hydrogen, or a pharmaceuticallyacceptable salt thereof.
 6. A compound of claim 3 wherein:R² ishydrogen, or a pharmaceutically acceptable salt thereof.
 7. A compoundof claim 3 wherein R¹ and R² are hydrogen, or a pharmaceuticallyacceptable salt thereof.
 8. The compound of claim 7 which is(3SR,4aRS,6SR,8aRS)-6-(1(2)H-tetrazole-5-yl)decahydroisoquinoline-3-carboxylicacid or a pharmaceutically acceptable salt thereof.
 9. The compound ofclaim 7 which is(3S,4aR,6S,8aR)-6-(1(2)H-tetrazole-5-yl)decahydroisoquinoline-3-carboxylicacid or a pharmaceutically acceptable salt thereof.
 10. The compound ofclaim 7 which is(3SR,4aRS,6SR,8aRS)-6-(3-hydroxyisoxazole-5-yl)decahydro-isoquinoline-3-carboxylicacid or a pharmaceutically acceptable salt thereof.
 11. The compound ofclaim 7 which is(3S,4aR,6S,8aR)-6-(3-hydroxyisoxazole-5-yl)decahydroisoquinoline-3-carboxylicacid or a pharmaceutically acceptable salt thereof.
 12. A method ofblocking the AMPA or the NMDA excitatory amino acid receptor in mammalwhich comprises administering to a mammal requiring decreased excitatoryamino acid neurotransmission a pharmaceutically-effective amount of acompound of claim
 1. 13. A method of blocking the AMPA or the NMDAexcitatory amino acid receptor in mammals which comprises administeringto a mammal requiring decreased excitatory amino acid neurotransmissiona pharmaceutically-effective amount of a compound of claim
 7. 14. Apharmaceutical formulation comprising a compound of claim 1 and apharmaceutically-acceptable carrier, diluent, or excipient.
 15. Aformulation according to claim 14 wherein the compound is6-(1(2)H-tetrazole-5-yl)decahydroisoquinoline-3-carboxylic acid or apharmaceutically acceptable salt thereof.
 16. A formulation according toclaim 14 wherein the compound is6-(3-hydroxyisoxazole-5-yl)decahydroisoquinoline-3-carboxylic acid or apharmaceutically acceptable salt thereof.